JP7429491B1 - Cetylpyridinium chloride hydrate-containing silicon nanoparticle composition and its application technology - Google Patents

Abstract

で示される（式中、Ａは、結合又は低級アルキレンを示し；Ｒ_１、Ｒ_２、Ｒ_３は、独立して、低級アルキル、O－Ｒ_５、フェニルを示し；Ｒ_５は、低級アルキル等を示し、Ｒ_４は、低級アルキル、低級アルケニル、フェニル等を示す。）。そのようなケイ素化合物と、セチルピリジニウム塩化物水和物とを含み、ナノ粒子の形態である組成物である。この組成物は、医療用材料や医療器具に良好に付着あるいは担持しやすい。
【選択図】なしThe present invention provides a composition in the form of nanoparticles that includes cetylpyridinium chloride hydrate and a specific silicon compound.
[Solution] A specific silicon compound is

(wherein A represents a bond or lower alkylene; R ₁ , R ₂ , R ₃ independently represent lower alkyl, O-R ₅ , phenyl; R ₅ represents lower alkyl, etc.) and R ₄ represents lower alkyl, lower alkenyl, phenyl, etc.). A composition comprising such a silicon compound and cetylpyridinium chloride hydrate is in the form of nanoparticles. This composition easily adheres to or is supported on medical materials and medical instruments.
[Selection diagram] None

Description

The present invention is a surfactant containing cetylpyridinium chloride hydrate and a silicon compound, which is effective for preventing and/or treating infectious diseases and against enveloped viruses in general, including the new coronavirus (SARS-Co-2). A composition comprising: The present invention also relates to a medical material and a medical material carrying the composition, and a novel drug delivery system using the medical material or medical device.

Cetylpyridinium chloride hydrate is a quaternary ammonium compound having a pyridine ring, and has strong bactericidal activity against Gram-positive bacteria including Staphylococcus, and also has bactericidal activity against other fungi. Due to its properties, it is used in medicines such as toothpastes, lozenges to disinfect the mouth, and gargles to disinfect the throat (Wikipedia).
Furthermore, cetylpyridinium chloride hydrate is known to be effective against enveloped viruses in general, including the new coronavirus (SARS-Co-2) (Non-Patent Document 1).

As of July 16, 2022, the novel coronavirus has infected more than 560 million people and killed more than 6 million people worldwide, and there is still no end in sight to the pandemic, which is shaking the world. It is. Although a number of therapeutic drugs have been developed, the primary response is vaccination, and supplementary preventive measures such as wearing a mask, washing hands, and avoiding crowds, close quarters, and close contact are widely recommended. These behaviors, other than hand washing, correspond to avoiding the risk of infection through inhalation of virus-containing droplets. Simulations have revealed the effects of humidity and the effectiveness of masks on the spread of droplets, and droplet infection has been positioned as the main route of infection.
On the other hand, the time period during which a virus attached to a material surface remains infectious is highly dependent on temperature and humidity, and there are reports that it remains infectious for up to a week at low temperatures and low humidity. Activation remains an important issue (Non-Patent Documents 2, 3). Alcohol and surfactants can destroy the envelope of enveloped viruses, including the new coronavirus, and their effectiveness remains the same even if the proteins on the surface of the virus mutate, so they can be expected to be effective against mutated viruses as well. Although wiping with surfactants is effective, it is difficult to do so frequently on items that people touch in public places, such as doorknobs, handrails, and straps. These agents are required to inactivate the antiviral effect in a short period of time and to maintain its sustainability.

There is also the problem of artificial joint infection. In general, as the elderly population increases, the number of patients with fractures and the number of surgeries associated with fractures are expected to increase. BACKGROUND ART In recent years, bone or joint surgeries using artificial joints have been on the rise, and it is reported that by 2030, the number of patients will be 4 million annually in the United States. However, in surgical operations using artificial joints, postoperative prosthetic joint infection (Prosthetic Joint Injection; PJI) may occur.
Prosthetic joint infections occur in approximately 1% of patients in Japan, and in approximately 1 to 2% of patients in the United States.
Many patients who develop artificial joint infections require multiple surgeries, which places a heavy burden on the patient, sometimes requiring amputation of the surgical site, and in the worst cases, death can occur. Diagnosis of artificial joint infection and treatment with drug administration are generally difficult, so sutures or cement containing antibiotics or antibiotics may be used, but their effectiveness is unclear and treatment costs are high.

In addition to artificial joint infections, postoperative infections, such as catheter-related bloodstream infections originating from internal catheters, and infections of the urinary tract and biliary tract, are also becoming a problem.
Under these circumstances, in medical settings such as orthopedics, surgery, and urology, medical materials containing antibacterial agents or bactericidal agents are used to prevent postoperative infections caused by medical materials or medical instruments. There is a strong desire for these drugs to have lasting effects, and attempts have been made to treat or prevent infectious diseases by loading medical materials or medical devices with medicinal ingredients using silicon compounds. Yes (Patent Documents 1 to 4).
However, none of the compositions described in this document allows for sterile filtration, and the medicinal ingredient is supported on medical materials or medical instruments by using a silicon compound in cetylpyridinium chloride hydrate. There is no mention of treating or preventing infectious diseases through sustained antibacterial and/or bactericidal effects. Note that there is Non-Patent Document 4 as a document showing a composition containing a drug and a silicon compound.

https://specchem-wako-jp.fujifilm.com/cpc/ C. Xie, H. Zao, K. Li, Z. Zhang, X. Lu, H. Pang, D. Wang, J. Chen, X. Zhng, D. Wu, Y. Gu, Y. Yuan, L. Zhang, and J. Lu, The evidence of indirect transmission of SARS- CoV-2 reported in Guangzhou, China BMC Public Health, 20. 2020, 1202. S. H. Bae, H. Shin, H-Y. Koo, S. W. Lee, J. M. Yang, and D. K. Yon, Asymptomatic transmission of SARS-Co-2 on evacuation flight, Emerg. Infect, Dis., 26, 2020, 2705. Journal of American Chemical Society, Vol. 125, No. 26, 2003, pp. 7860-7865

Special Publication No. 2007-505697 Japanese Patent Application Publication No. 2008-266157 Special Publication No. 2008-506493 Special table 2012-533568 publication

One of the problems to be solved by the present invention is to incorporate cetylpyridinium chloride hydrate into sanitary materials such as masks, gloves, gauze, surgical tape, and various preventive shielding plates as a countermeasure against the new coronavirus infection. To provide a new virus detection and capture device by utilizing the effect of preventing infection by viruses that come into contact with water. The next challenge is to provide a novel drug delivery system in which cetylpyridinium chloride hydrate is stably supported on medical materials or medical devices, and which exhibits a sustained antibacterial/or bactericidal effect after indwelling in a living body. That's true.

As a result of extensive research, the present inventors discovered that the above problems could be solved by creating a nanoparticle composition in which cetylpyridinium chloride hydrate was contained in a specific silicon compound, and the present invention was realized. completed. That is, the basic idea of the present invention is a composition containing cetylpyridinium chloride hydrate and a specific silicon compound, which is in the form of nanoparticles. The nanoparticle form exhibits high adhesion or retention properties to medical instruments and the like, and also enables sterile filtration, which is required for medical instruments.

The present invention includes the embodiments illustrated below.
Item 1.

[In formula (I),
A represents a bond or lower alkylene; R1, R2 and R3 are each independently,
(1) Lower alkyl,
(2) O-R5, or (3) represents phenyl;
R5 is
(1) Lower alkyl, or (2) lower alkanoyl;
R4 is
(1) Lower alkyl,
(2) lower alkenyl,
(3) Phenyl,
(4) Amino which may be substituted with the same or different 1 to 2 R6,
(5) R5-CONH, or (6) indicates cyano;
R6 is
(1) Lower alkyl which may be substituted with the same or different 1 to 2 R7s,
(2) Amino which may be substituted with the same or different 1 to 2 R8s,
(3) Indicates silyl lower alkyl which may be substituted with the same or different 1 to 3 lower alkoxy groups.
R7 is
(1) Amino which may be substituted with the same or different 1 to 2 lower alkyls,
(2) phenyl optionally substituted with hydroxy;
(3) Carbamoyl,
(4) imidazolyl optionally substituted with benzyl, or (5) carboxy;
R8 is
(1) Amino lower alkyl (herein, amino may be substituted with 1 to 2 lower alkyls that are the same or different),
Two R8s may be combined with the nitrogen to which they are bonded to form a monocyclic or bicyclic heterocycle; or a salt thereof.
Here, the compound of general formula (I) may be two or more different types of compounds represented by general formula (I).

Item 2. The compound of formula (I) is
A represents a bond or C1-6 alkylene;
R1, R2 and R3 are each independently,
(1) C1-6 alkyl,
(2) O-R5, or (3) indicates phenyl;
R5 is
(1) C1-6 alkyl, or (2) C1-6 alkanoyl,
R4 is (1) C1-8 alkyl,
(2) C2-4 alkenyl,
(3) Phenyl,
(4) amino optionally substituted with one R6,
(5) R6-CONH, or (6) indicates cyano;
R6 is
(1) C1-6 alkyl which may be substituted with the same or different 1 to 2 R7s,
(2) Amino which may be substituted with the same or different 1 to 2 R8, or (3) Silyl-C-1-6 alkyl which may be substituted with the same or different 1 to 3 C1-6 alkoxy. Show;
R7 is
(1) Amino which may be substituted with the same or different 1 to 2 C1-6 alkyl,
(2) phenyl substituted with hydroxy,
(3) Carbamoyl,
(4) represents benzylimidazolyl, or (5) carboxy;
R8 represents amino-C1-6 alkyl (wherein amino may be substituted with the same or different 1-2 C1-6 alkyl); or two R8s together with the nitrogen to which they are bonded The compound according to item 1, which may form a saturated or unsaturated 3- to 12-membered simple or bicyclic heterocycle containing at least one nitrogen as a ring-constituting heteroatom. Composition.

Item 3. 3. The composition according to item 1 or 2, wherein the compound of formula (I) is a compound in which R4 is R6-CONH.

Item 4. The compound of general formula (I)
A represents C1-6 alkylene;
R1, R2 and R3 each independently represent O-R5;
R5 represents C1-6 alkyl;
R4 indicates R6-CONH;
R6 is
(1) C1-6 alkyl which may be substituted with the same or different 1 to 2 R7s, or (2) amino which may be substituted with the same or different 1 to 2 R8s;
R7 is
(1) Amino which may be substituted with two same or different C1-6 alkyls,
(2) phenyl substituted with hydroxy,
(3) Carbamoyl,
(4) Benzyl imidazolyl,
(5) Shows carboxylic acid;
Item 3, wherein R8 is a compound representing amino-C1-6 alkyl (herein, amino may be substituted with the same or different 1 to 2 C1-6 alkyl). Composition.

Item 5. The composition according to any one of Items 1 and 4, wherein the particle size of the composition is 300 nm or less.

Section 6. Infectious diseases, such as surgical site infections, prosthetic joint infections, urinary tract infections, urinary tract infections, biliary tract infections, bloodstream infections, pneumonia, diabetic foot infections, oral infections, or skin infections. Item 6. The composition according to any one of Items 1 to 5, for the prevention/or treatment of a disease.

Item 7. The composition according to any one of Items 1 to 6, for supporting on medical materials, medical instruments, or biological components.

Item 8. The composition according to any one of Items 1 to 7, wherein cetylpyridinium chloride hydrate can continuously exhibit an antibacterial or bactericidal effect.

Item 9. The composition according to any one of Items 1 to 8, which can be subjected to sterile filtration.

Item 10. A medical material or medical device carrying the composition according to any one of Items 1 to 9.

Item 11. A compound of general formula (I) or a salt thereof according to any one of Items 1 to 4, which is mixed with cetylpyridinium chloride hydrate and supported on medical materials, medical instruments, or biological components. A compound or a salt thereof that enables the antibacterial or bactericidal effect of an antibacterial agent or bactericidal agent to be exerted in a sustained manner.

Item 12. Infectious diseases can be prevented by carrying the composition according to any one of Items 1 to 9 in a medical material or medical device and indwelling it in a living body, or by spraying or applying the composition to biological components. Methods of prevention and/or treatment.

Item 13. A method for producing the composition according to any one of Items 1 to 9, comprising the following steps:
Step 1: Forming micelles using an anionic surfactant and a nonionic surfactant;
Step 2: A step of adding cetylpyridinium chloride hydrate and a silicon compound represented by formula (I) or a salt thereof to the micelles obtained in Step 1;
Step 3: removing excess reagent by dialysis to obtain a composition; and Step 4: sterile filtering the composition obtained in Step 3.

In the present invention, by mixing cetylpyridinium chloride hydrate with a silicon compound to form nanoparticles, it becomes possible to efficiently encapsulate and remove the drug in the composition. Compositions of the invention may be in the form of nanoparticles having a particle size that allows sterile filtration. The composition of the present invention can also be applied to medical materials, medical instruments, or biological components to continuously demonstrate the medicinal effects of cetylpyridinium chloride hydrate, such as antiviral activity, antibacterial activity, and bacterial adhesion inhibiting effect. It can exert a growth-inhibiting effect, thereby preventing and/or treating infections in the surgical field and/or the postoperative affected area.

The present invention includes the specific embodiments illustrated below, and also includes any combination of the specific embodiments.

The lower alkyl in this specification includes a straight or branched alkyl group having 1 to 8 carbon atoms (C1-8). More specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, n-hexyl, 1, Includes 2,2-trimethylpropyl, 3,3-dimethylbutyl, 2-ethylbutyl, isohexyl, 3-methylpentyl, n-heptyl, isoheptyl, n-octyl, isooctyl, and the like. Preferred lower alkyl is C1-6 alkyl.

In the present specification, the lower alkylene includes a linear or branched divalent hydrocarbon group having 1 to 8 carbon atoms (C1-8 alkylene). More specifically, for example, methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, n-pentylene, ethylpropylene, isopentylene, n-hexylene, 2-ethylbutylene, isohexylene, 3-methylpentylene, Includes n-heptylene, isoheptylene, n-octylene, isooctylene, and the like. Preferred lower alkylene is C1-6 alkylene, more preferably C1-3 alkylene.

As used herein, the lower alkenyl includes straight chain or branched alkenyl groups having 1 to 3 double bonds and having 2 to 6 carbon atoms (C2-6 alkenyl), trans form ((E form) ) and cis form ((Z form)). More specifically, for example, vinyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-butenyl, 1-butenyl, 3-butenyl. , 2-pentenyl, 1-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-butadienyl, 1,3-pentadienyl, 2-penten-4-yl, 2-hexenyl, 1-hexenyl, 5-hexenyl, 3- Included are hexenyl, 4-hexenyl, 3,3-dimethyl-1-propenyl, 2-ethyl-1-propenyl, 1,3,5-hexatrienyl, 1,3-hexadienyl, 1,4-hexadienyl groups, and the like. Preferred lower alkenyl is C2-4 alkenyl.

As the lower alkanoyl in this specification, a linear or branched alkanoyl group having 1 to 6 carbon atoms (C1-6 alkanoyl) can be mentioned. More specifically, it includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl, hexanoyl, and the like. Preferred lower alkanoyl is C1-4 alkanoyl.

In the present specification, lower alkoxy includes a linear or branched alkoxy (lower alkyl-O-) group having 1 to 8 carbon atoms (C1-8 alkoxy). More specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 1-ethylpropyloxy, isopentyloxy, neopentyloxy , n-hexyloxy, 1,2,2-trimethylpropyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy, isohexyloxy, 3-methylpentyloxy, n-heptyloxy, isoheptyloxy, n -Includes octyloxy, isooctyloxy, etc. Preferred lower alkoxy is C1-6 alkoxy, more preferably C1-3 alkoxy.

In the present specification, the heterocycle refers to a saturated or unsaturated 3- to 12-membered monocyclic ring containing 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur as ring constituent atoms. Or a polycyclic heterocycle can be mentioned. An "unsaturated" ring refers to an aromatic ring or a ring in which the bonds between ring atoms are partially hydrogenated. Specifically, the heterocycle includes, for example, a saturated or unsaturated 3- to 12-membered monocyclic or bicyclic heterocycle containing at least one nitrogen as a ring-constituting heteroatom. More specifically, for example, pyrrole, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazole, dihydrotriazine, azetidine, pyrrolidine, imidazolidine, piperidine, pyrazoline, piperazine, azepane, 1,4- Diazepane, indole, indoline (dihydroindoline), isoindole, isoindoline (dihydroisoindoline), benzimidazole, dihydrobenzimidazole, indazole (dihydroindazole), indazoline, quinoline, dihydroquinoline, tetrahydroquinoline, benzotriazole, tetrazolopyridine , tetrazolopyridazine, isoquinoline, dihydroisoquinoline, dihydrotriazine, imidazopyridine, naphthyridine, tetrahydronaphthyridine, hexahydronaphthyridine, cinnoline, quinoxaline, dihydroquinoxaline, tetrahydroquinoxaline, quinazoline, dihydroquinazoline, tetrahydroquinozoline, pyrazolopyridine, hexahydro Includes pyrimidopyridine (1,5,7-triazapicyclo[4.4.0]dec-5-ene) and the like. A preferred heterocycle is a saturated or unsaturated 3- to 12-membered bicyclic heterocycle containing at least one nitrogen as a ring heteroatom.

Compositions herein may include cetylpyridinium chloride hydrate and a silicon compound. Cetylpyridinium chloride hydrate only needs to be chemically or physically mixed with one or more silicon compounds, for example, encapsulated or encapsulated in a silicon compound, or chemically bonded to a silicon compound, Liquid, particulate or encapsulated nanoparticle compositions may be formed. Cetylpyridinium chloride hydrate can exhibit sustained virus inactivation effect and antibacterial or bactericidal activity by forming a nanoparticle composition with the silicon compound of general formula (I).

The silicon compound in this specification is a compound represented by formula (I) (hereinafter also referred to as compound (I)), and includes geometric isomers, stereoisomers, optical isomers, and tautomers. Various isomers may be separated and purified, for example, by general optical resolution methods, or may be produced from appropriate optically active raw material compounds.

Cetylpyridinium chloride hydrate and compound (I) may form an acid addition salt or a base addition salt depending on the type of substituent. Examples of acids that form acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid; and gluconic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, Examples include maleic acid, fumaric acid, malic acid, and lactic acid. Examples of bases that form base addition salts include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; methylamine, diethylamine, triethylamine, and ethanol. Organic bases such as amine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyrodine, picoline, choline; and ammonium salts. Antiviral and antibacterial or bactericidal agents and salts of compound (I) can be produced by subjecting them to a conventional salt-forming treatment.

The compositions herein may be used for the prevention and/or treatment of infectious diseases, such as those caused by viruses and bacteria, anaerobes or drug-resistant bacteria. Viruses include the new coronavirus (COVID-19), enveloped viruses including influenza viruses, bacteria, anaerobic bacteria, and drug-resistant bacteria include gram-positive bacteria, gram-negative bacteria, staphylococci, enterococci, Escherichia coli, and methicillin-free bacteria. Mention may be made of susceptible bacteria, vancomycin non-susceptible bacteria, penicillin non-susceptible bacteria, clarithromycin non-susceptible bacteria or metronidazole non-susceptible bacteria, more specifically for example Methicillin-resistant Staphylococcus aureus, excreted Efflux-related: Methicillin-resistant Staphylococcus aureus, Vancomycin- intermediate Staphylococcus aureus, Hetero-vancomycin- intermediate Staphylococcus aureus, These include Vancomycin-resistant Staphylococcus aureus, Vancomycin-resistant Enterococci, etc. Infections include, but are not limited to, surgical site infections (e.g., surgical wound infections), prosthetic joint infections, urinary tract infections, biliary atresia, bloodstream infections (e.g., sepsis), and pneumonia. (eg, nosocomial or community-acquired pneumonia), diabetic foot infections, and skin infections such as cellulites, boils, abscesses, styes, and impetigo.

The composition herein may be supported by chemically or physically attached or bonded to medical materials or medical instruments, or applied to biological components at the surgical site, surgical field, or postoperatively affected area. good. The composition may be supported by coating or spraying a solution of the composition, such as an aqueous solution, onto a medical material or device or an oral biocomponent.

The compositions herein include solutions, injections, sprays, aerosols, lotions, ointments, creams, gels, patches, tapes, and poultices in combination with pharmaceutically acceptable carriers. It can be made into a formulation such as Pharmaceutically acceptable carriers include activators such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; water, ethanol, propanol, simple syrup, glucose solution, and starch solution. , gelatin solution, carboxymethylcellulose, shellax, methylcellulose, potassium phosphate, polyvinylpyrrolidone, and other binders; purified talc, stearate, boric acid powder, polyethylene glycol, and other lubricants.

Examples of medical materials in this specification include titanium metal, ceramics, functional resins, functional plastics, polyurethane, polyvinyl chloride, cotton, silk, linen, nonwoven fabrics, and the like.

The medical device herein is an artificial medical device that can be implanted and/or indwelled in the body, and is manufactured from medical materials. Medical devices include, for example, catheters, pacemakers, grafts, stents, wires, guide wires, orthopedic implants, medical implants, body implants, implantable diffusion pumps, inlets, heart valves, artificial joints, aortic grafts, Mention may be made of blood oxygenation membranes, blood oxygenator tubing, dialysis membranes, drug delivery systems, endoprostheses, endotracheal tubes, aortic balloons, vascular grafts, vascular tubing, arterial tubing, and venous tubing.

As used herein, biological components include skin, bones (e.g., joints), organs (e.g., urinary tract, biliary tract, lungs), etc., and are preferably biological components at the surgical site, surgical field, or postoperatively affected area. .

Aseptic filtration in this specification refers to filtration using a filter with a pore size (for example, 0.2 to 0.45 μm) through which bacteria and the like cannot pass, preferably a filter with a pore size of 0.22 μm, and is preferably ultrafiltration. The compositions herein may have a particle size that allows for sterile filtration. The average particle size of the composition can be measured, for example, by a dynamic light scattering method, and is, for example, 300 nm or less, preferably 10 to 250 nm, more preferably 50 to 230 nm.

[General manufacturing method of silicon compound (I)]
The silicon compound represented by formula (I) may be a commercially available one, or may be newly produced according to a conventional method in the art, for example, the production method shown below. The method for producing the compound represented by formula (I) is not limited to the production method shown below. In the production method described below, each raw material compound may form a salt as long as it does not inhibit the reaction, and as such a salt, those exemplified as the salt of compound (I) may be used. When a raw material compound is not described in a specific production method, a commercially available compound may be used, or a compound produced according to a method known per se or a method analogous thereto may be used. In each reaction in the following production method, the product can be used in the next reaction as a reaction solution or as a crude product, can be isolated from the reaction mixture according to conventional methods, or can be easily isolated by conventional separation means. It can also be purified. Usual separation means include, for example, extraction, concentration, crystallization, filtration, recrystallization, distillation, and various types of chromatography. The product obtained by the following production method may be isolated and purified as r-free compound, its salt or solvate. In the following production method, when performing an alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, ureation reaction, etherification reaction, oxidation reaction, reduction reaction, etc., these reactions are known per se. It can be carried out according to the method or a method similar thereto. Examples of such methods include, for example, ORGANIC FUNCTIONAL GROUP PREPARATION, 2nd edition, published by ACADEMIC PRESS, INC. in 1989; Comprehensive Organic Transformations. (Comprehensive Organic Transformations) published by VCH Publishers Inc., 1989; methods described in "Greene's Protective Groups in Organic Synthesis" by PGM Wuts and TW Greene (4th edition, 2006), etc. .

[General manufacturing method 1 (amidation reaction) of silicon compound (I)]
[In the formula, each symbol is as described in this specification]
Compound (Ia) can be obtained by amidation of compound (II) and compound (III).
Amidation can be carried out by a method commonly used by those skilled in the art.
Compound (Ia) is compound (II) or its reactive derivative at the carboxy group and compound (III)
Alternatively, it may be produced by reacting its reactive derivative at the amino group.

Examples of reactive derivatives at the carboxyl group of compound (11) include acid halides, acid azides, acid anhydrides, activated amides, activated esters, and the like. Suitable examples of reactive derivatives include acid chlorides, acid azides; substituted phosphoric acids such as dialkyl phosphoric acids, phenyl phosphates, diphenyl phosphoric acids, dibenzyl phosphoric acids, halogenated phosphoric acids, dialkyl phosphorous acids, Sulfonic acids such as sulfurous acid, thiosulfuric acid, sulfuric acid, methanesulfonic acid, aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, piperic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, or Mixed acid anhydrides with acids such as aromatic carboxylic acids such as benzoic acid; symmetric acid anhydrides; activated amides with imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles; for example cyanomethyl esters, Activated esters such as methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester; for example, N, Examples include esters with N-hydroxy compounds such as N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysucciimide, N-hydroxyphthalimide, and HOBt. These reactive derivatives can be arbitrarily selected from among them depending on the chemical properties of compound (II) to be used.

When compound (II) is used in the above reaction in the form of a free acid or a salt thereof, it is desirable to carry out the reaction in the presence of a condensing agent. As the condensing agent, a wide range of substances known in this field can be used, such as DCC; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; diethylcarbodiimide; -N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; WSC or its HCl salt; N-N'-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexyl imine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride ; Lower alkyl haloformates, such as ethyl chloroformate and isopropyl chloroformate; Triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium Hydroxide inner salt; benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; DMF and thionyl chloride, phosgene , the so-called Vilsmeier test prepared by reaction with trichloromethyl chloroformate, phosphorus oxychloride, and the like. Further, it is more desirable to carry out the reaction in the presence of the above-mentioned condensing agent and in the coexistence of an activated ester such as N-hydroxysuccinimide, N-hydroxyphthalimide, HOBt, or the like.

Suitable reactive derivatives of the amino group of compound (III) include Schiff base-type imino or its enamine-type tautomer formed by the reaction of compound (III) with a carbonyl compound such as an aldehyde, ketone, etc.; Compound Silyl derivatives produced by the reaction of (III) with silyl compounds such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea, etc.; Reaction of compound (III) with phosphorus trichloride or phosgene, etc. Examples include reactive derivatives produced by.

This reaction can usually be carried out in a conventional solvent that does not adversely affect the reaction. Examples of solvents include water; alcohol solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, and ethylene glycol; ketone solvents such as acetone and methyl ethyl ketone; THF, dioxane, Et2O, diisopropyl ether, and diglyme. Ether solvents such as AcOMt, AcOEt, etc.; Aprotic solvents such as MeCN, DMF, DMSO; Hydrocarbon solvents such as n-pentane, n-hexane, n-hebutane, cyclohexane; Methylene chloride , ethylene chloride, halogenated hydrocarbon solvents such as DCM; other organic solvents, or mixed solvents thereof.

This reaction may be performed in the presence of a base. As the base, a wide variety of known inorganic bases and organic bases can be used. Examples of inorganic bases include alkali metals (e.g., sodium, potassium, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., LiOH, NaOH, etc.). , KOH etc.), alkali metal carbonates (e.g. Li2CO3, Na2CO3, K2CO3, Cs2CO3 etc.), alkali metal lower alkoxides (e.g. sodium methoxide, sodium ethoxide etc.), alkali metal hydrides (e.g. NaH, KH etc.) Can be mentioned. Examples of organic bases include trialkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN. , DABCO, DBU, etc. Furthermore, when these bases are in liquid form, they can also be used as a solvent. These bases may be used alone or in combination of two or more. The amount of the base used is usually 0.1 to 10 mol, preferably 0.1 to 3 mol, per 1 mol of compound (II).

The ratio of Compound (II) and Compound (III) used in General Production Method 1 is usually at least 1 mol, preferably 1 to 5 mol, of the former per 1 mol of the latter. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. Preferably, the reaction is carried out under a temperature condition of room temperature to 100°C, for example, for 30 minutes to 30 hours, preferably 30 minutes to 5 hours. In addition, when compound (1a) has an N-protecting group, conventional methods such as hydrolysis and hydrogenolysis can be applied to the elimination reaction of the N-protecting group.

[General manufacturing method 2 of silicon compound (I) (urea formation reaction)]

[In the formula, each symbol is as described in this specification]
Compound (Ib) can be obtained by ureation of compound (IV) and compound (V). For the urea conversion, urea conversion commonly used by those skilled in the art can be employed. This reaction can usually be carried out in an inert solvent that does not adversely affect the reaction. Examples of inert solvents include the ketone solvents, ether solvents, alcohol solvents, ester solvents, aprotic solvents, and halogenated hydrocarbon solvents described in General Production Method 1; or other organic solvents, or mixed solvents thereof. , water, etc.
This reaction may be carried out in the presence of a base, if necessary. As the base, the base described in General Production Method 1 can be used. These bases may be used alone or in combination of two or more. The amount of the base used is usually 0.1 to 10 mol, preferably 0.1 to 3 mol, per 1 mol of compound (IV).
The ratio of compound (IV) and compound (V) used in General Production Method 2 is usually at least 1 mol, preferably about 1 to 5 mol, of the former per 1 mol of the latter.
The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. Preferably, the reaction is carried out at a temperature of room temperature to 100° C., for example, for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

[General manufacturing method of drug-containing silicon nanoparticle composition]
The composition of the present invention can be produced by mixing cetylpyridinium chloride hydrate and silicon compound (I), for example, according to the method described in Non-Patent Document 1. Specifically, the method for producing the composition of the present invention includes the following steps.
Step 1. Formation of micelles Anionic surfactants, such as aerosol OT (AOT; dioctyl sodium sulfosuccinate) and nonionic surfactants, such as 1-butanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,6- A diol such as hexanediol is dissolved in water and mixed with vigorous stirring to form micelles.
Step 2. Formation of drug-micelles Drug-micelle formation is performed by adding and mixing a drug (i.e., an antibacterial agent or bactericide) dissolved in N,N-dimethylformamide (DMF) to the micelles obtained in step 1. Form micelles.
Step 3. Formation of drug-silica micelles A silicon compound is added to the drug-micelle obtained in step 2 and the mixture is stirred to form drug-silica micelles. Here, one or more different silicon compounds may be added simultaneously or separately.
Step 4. Dialysis After forming drug-silica micelles in step 3, the surfactant, solvent, and excess reagent are removed by dialysis to obtain drug-silica nanoparticles.
Step 5. Sterile Formulation The drug-silica nanoparticles obtained in step 4 are filtered through a sterile filter to obtain a sterilized composition.

The composition of the present invention obtained as described above is coated on medical materials or medical instruments, or biological components in the surgical field or the affected area after surgery, and specifically, it is supported by a dipping method, a spraying method, etc. be able to.

The present invention will be explained in more detail with reference to Reference Examples, Production Examples, Examples, and Experimental Examples below, but the present invention is not limited by these.
In this specification, the following abbreviations may be used.
STR : Structural formula
DBN: 1,5-diazabicyclo[4.3.0]noner-5-ene
DABCO: 1,4-diazabicyclo[2.2.2]octane
DBU: 1,8-diazabicyclo[5.4.0]-7-undecene
HOBt: 1-Hydroxybenzotriazole DCC: Dichlorohexylcarbodiimide WSC: 3-Ethyl-1-(3-methylaminopropyl)carbodiimide AcOMt: Methyl acetate AcOEt: Ethyl acetate MeCN: Acetonitrile MeOH: Methanol EtOH: Ethanol THF: Tetrahydrofuran DCM: Dichloromethane DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide Et2O: Diethyl ether Hexane: Hexane LiOH: Lithium hydroxide NaOH: Sodium hydroxide KOH: Potassium hydroxide NaH: Sodium hydride KH: Potassium hydride Li2CO3: Lithium carbonate Na2CO3: Sodium carbonate K2CO3: Potassium carbonate Cs2CO3: Cesium carbonate AOT: Dioctyl sodium sulfosuccinate
Z-Asp(OBzl)-OH: (S)-4-(benzyloxy)-2-benzyloxycarbonylamino)-4-oxobutanoic acid
Z-Asp-obzl: (S)-4-(benzyloxy)-2-benzyloxycarbonylamino)-4-oxobutanoic acid Z-His(Bzl)-OH: (S)-3-(1-benzyl-1H- Imidazole-4-
yl)-2-(benzyloxycarbonylamino)propionic acid
Pd-C: Palladium on carbon TLC: Thin layer chromatography "Room temperature" in the following examples usually refers to about 10°C to 35°C. Ratios shown in mixed solvents indicate volume ratios unless otherwise specified. % indicates weight % unless otherwise specified.
1HNR (proton nuclear magnetic resonance spectrum) is a Fourier transform type NMR at room temperature.
(Bruker AVANCE 300 (300MHz), Bruker AVANCE III 400 (400MHz), and
Bruker AVANCE III 500 (500MHz)).

[Reference example] Production of silicon compound intermediates Silicon compound intermediates. Table 1 shows the structures and names of the synthesized compounds.

Reference example 1: Synthesis of compound (1)

Dissolve 836 mg of Z-Asp(OBzl)-OH and 16.3 mg of HOBt in 10 ml of dichloromethane, add 0.41 ml of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide, stir for a while, and then add 0.5 ml of 3-Aminopropyl-triethoxysilane. ml and stirred at room temperature. The reaction solution was purified using a Florisil column (eluent: Hexane: CH2Cl2 = 1:1-0:1) to obtain 837 mg of compound (1) as a colorless solid.

1H NMR (CDCl3, 400 MHz) δ 0.60 (m, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.58 (m, 2 H), 2.72 (dd, J = 17.2 Hz, 6.4 Hz, 1 H), 3.14 (dd, J = 17.2 Hz, 4.2 Hz, 1 H), 3.22 (m, 2 H), 3.81 (q, J = 7.0 Hz, 6 H), 4.55 (m, 1 H), 5.06 −5.17 (m, 4 H), 5.91 (d, J = 7.7 Hz, 1 H), 6.53 (m, 1 H), 7.28−7.45 (m, 10 H).

Reference example 2: Synthesis of compound (2)

Dissolve 836 mg of Z-Asp-obzl and 16.3 mg of HOBt in 10 ml of dichloromethane, add 0.41 ml of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide, stir for a while, add 0.5 ml of 3-Aminopropyltriethoxysilane, and let the mixture cool to room temperature. It was stirred with The reaction solution was purified using a Florisil column (eluent: Hexane: CH2Cl2 = 1:1-0:1) to obtain 649 mg of compound (2) as a colorless solid.

1H NMR (CDCl3, 400 MHz) δ 0.60 (m, 2 H), 1.21 (t, J = 7.0 Hz, 9 H), 1.58 (m, 2 H), 2.69 (dd, J = 5.7 Hz, 4.1 Hz, 1 H), 2.91 (dd, J =5.7 Hz, 4.1 Hz, 1 H), 3.19 (m, 2 H), 3.81 (q, J = 7.0 Hz, 6 H), 4.61 (m, 1 H), 5.10 (s, 2H), 5.18 (dd, J =16.0 Hz, 12.3 Hz, 2 H), 5.78 (bs, 1 H), 6.08 (d, J = 8.8 Hz, 1 H), 7.28−7.38 (m, 10 H).

Reference example 3: Synthesis of compound (3)

281 mg of 3-Aminopropyltriethoxysilane, 400 mg of N-CBZ-L-tyrosine, and 9.7 mg of HOBt were dissolved in 10 ml of dichloromethane, 197 mg of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide was added, and the mixture was stirred at room temperature for 1 hour.
The reaction solution was purified using a Florisil column (eluent: CH2Cl2:EtOH = 20:1) to obtain 31 mg of compound (3) as a colorless solid.

1H NMR (CDCl3, 400 MHz) δ 0.60-0.68 (m, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.45-1.50 (m, 2 H), 2.85-3.25 (m, 4 H ), 3.80 (q, J = 7.0 Hz, 6 H), 4.21-4.33 (m, 1 H), 5.09 (d, J =3.0 Hz, 2 H), 5.40 (br-s, 1 H), 5.79 ( br-s, 1 H), 5.85 (br-s, 1 H), 6.74 (d, J = 8.5 Hz, 2 H), 7.03(br-d, 2 H), 7.29-7.36 (m, 5 H) .

Reference example 4: Synthesis of compound (4)
942 mg of 1-Aminopropyltriethoxysilane, 1193 mg of N-Carbobenzyloxy-L-glutamine, and 32.6 mg of HOBt were dissolved in 10 ml of dichloromethane, 727 mg of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified using a Florisil column (eluent: CH2Cl2:EtOH = 20:1) to obtain 700 mg of compound (4) as a white solid.

1H NMR (DMSO-d6, 400 MHz) δ 0.60-0.68 (m, 2 H), 1.14 (t, J = 7.0 Hz, 9 H), 1.39-1.48 (m, 2 H), 1.62-1.75 (m, 1 H), 1.79-1.89 (m, 1 H), 2.00-2.15 (m, 3 H), 2.94-3.07 (m, 3 H), 3.73 (q, J = 7.0 Hz, 6 H), 3.86-3.95 (m, 1 H), 6.75 (s, 1 H), 7.25 (s, 1 H), 7.26−7.45 (m, 5 H), 7.85 (t, J = 5.4 Hz, 1 H).

Reference example 5: Synthesis of compound (5)

534 mg of 2-Aminopropyltriethoxysilane, 1000 mg of N,N'-Dicarbobenzyloxy-L-lysine, and 18.5 mg of HOBt were dissolved in 10 ml of dichloromethane, 412 mg of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide was added, and the mixture was stirred at room temperature for 1 hour. . The reaction solution was purified using a Florisil column (eluent: CH2Cl2:EtOH = 20:1) to obtain 570 mg of compound (5) as a white solid.

1H NMR (CDCl3, 400 MHz) δ 0.62 (br-t, J = 7.8 Hz, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.32-1.42 (m, 2 H), 1.47-1.56 (m, 2 H), 1.58-1.69 (m, 2 H), 1.80-1.92 (m, 1 H), 3.10-3.30 (m, 4 H), 3.81 (q, J = 7.0 Hz, 6 H), 4.04-4.13 (m, 1 H), 4.85 (br-s, 1 H), 5.01-5.17 (m, 4 H), 5.48 (br-d, J = 6.4 Hz, 1 H), 6.23 (br-s , 1 H), 7.27-7.40 (m, 10 H).

Reference example 6: Synthesis of compound (6)

942 mg of 3-Aminopropyltriethoxysilane, 1695 mg of Z-His(Bzl)-OH, and 33 mg of HOBt were dissolved in 10 ml of dichloromethane, 727 mg of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified using a Florisil column (eluent: CH2Cl2) to obtain 1520 mg of compound (6) as a white solid.

1H NMR (CDCl3, 400 MHz) δ 0.50 (br-t, J = 6.1 Hz, 2 H), 1.21 (t, J = 7.0 Hz, 9 H), 1.45-1.55 (m, 2 H), 2.86-2.94 (m, 1 H), 3.09-3.19 (m, 3 H), 3.80 (q, J = 7.0 Hz, 6 H), 4.44 (br-s, 1 H), 5.02 (s, 2H), 5.11 (d , J = 2.0 Hz, 2 H), 6.71 (br-s, 2 H), 6.93 (br-s, 1 H ), 7.10-7.15 (m, 2 H), 7.28-7.42 (m, 10 H).

Reference example 7: Synthesis of compound (7)

942 mg of 4-Aminopropyltriethoxysilane, 1045 mg of Z-His(Bzl)-OH, and 33 mg of HOBt were dissolved in 10 ml of dichloromethane, 727 mg of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified using a Florisil column (eluent: CH2Cl2) to obtain 1100 mg of compound (7) as a white solid.

1H NMR (CDCl3, 400 MHz) δ 0.63 (br-t, J = 7.9 Hz, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.58-1.67 (m, 2 H), 2.39 (t , J = 5.8 Hz, 2 H), 3.24 (dd, J = 12.8 Hz, 6.8 Hz, 2 H), 3.48 (dd, J = 12.0 Hz, 6.1 Hz, 2 H), 3.81 (q, J = 7.0 Hz , 6H), 5.09 (s, 2H), 5.48 (br-s, 1H), 5.85 (br-s, 1H), 7.29-7.40 (m, 5H).

Reference example 8: Synthesis of compound (8)

942 mg of 5-Aminopropyltriethoxysilane, 1111 mg of 4-Benzyloxycarbonylamino-butyric acid, and 33 mg of HOBt were dissolved in 10 ml of dichloromethane, 727 mg of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was purified using a Florisil column (eluent: CH2Cl2) to obtain 1600 mg of compound (8) as a white solid.

1H NMR (CDCl3, 400 MHz) δ 0.64 (br-t, J = 8.2 Hz, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.57-1.73 (m, 5 H), 1.80-1.88 (m, 2 H), 2.17-2.23 (m, 4 H), 2.36 (t, J = 6.4 Hz, 1 H), 3.13-3.28 (m, 6 H), 3.81 (q, J = 7.0 Hz, 6 H), 5.09 (s, 2H), 5.14 (br-s, 1H), 6.09 (br-s, 1H), 7.30-7.42 (m, 5H).

Reference example 9: Synthesis of compound (9)

471 mg of 6-Aminopropyltriethoxysilane, 487 mg of 4-(benzyloxy)-4-oxobutanoic acid, and 16 mg of HOBt were dissolved in 10 ml of dichloromethane, 363 mg of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified using a Florisil column (eluent: CH2Cl2) to obtain 590 mg of compound (9) as a colorless oil.

1H NMR (CDCl3, 400 MHz) δ 0.63 (t, J = 8.0 Hz, 2 H), 1.23 (t, J = 7.0 Hz, 9 H), 1.57-1.67 (m, 2 H), 2.47 (t, J = 6.9 Hz, 2 H), 2.73 (t, J = 6.9 Hz, 2 H), 3.24 (q, J = 6.9 Hz, 2 H), 3.82 (q, J = 7.0 Hz, 6 H), 5.13 (s , 2H), 5.87 (br-s, 1H), 7.29-7.43 (m, 5H).

[Production Example] A silicon compound was produced by the method described below. Table 2 shows the structures and names of the synthesized compounds.

Production example 1: Synthesis of compound (10)

980 mg of compound (1) was dissolved in 20 ml of ethanol, 218 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After 2 hours, disappearance of the raw material was confirmed by TLC, and 539 mg of compound (10) was obtained as a colorless amorphous substance by filtration through Celite and concentration.

1H NMR (CD3CD2OD, 400 MHz) δ 0.60 (m, 2 H), 1.20 (t, J = 7.0 Hz, 9 H), 1.61 (m, 2 H), 2.51 (dd, J = 16.8 Hz, 9.8 Hz, 1 H), 2.64 (dd, J = 16.8 Hz, 4.7 Hz, 1 H), 3.20 (t, J = 7.2 Hz, 2 H), 3.81 (q, J =

Production example 2: Synthesis of compound (11)

645 mg of compound (2) was dissolved in 15 ml of ethanol, 130 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After 2 hours, disappearance of the raw material was confirmed by TLC, and 368 mg of compound (11) was obtained as a colorless amorphous substance by filtration through Celite and concentration.

1H NMR (CD3CD2OD, 400 MHz) δ 0.61 (m, 2 H), 1.20 (t, J = 7.0 Hz, 9 H), 1.61 (m, 2 H), 2.60 (dd, J = 16.4 Hz, 9.8 Hz, 1 H), 2.92 (dd, J = 16.4 Hz, 3.4 Hz, 1 H), 3.16 (m, 2 H), 3.73 (dd, J = 9.8 Hz, 3.4 Hz, 1H), 3.81 (q, J = 7.0 Hz, 6H).

Production example 3: Synthesis of compound (12)

1,5,7-Triazabicyclo[4.4.0]dec-5-ene (1000 mg) was dissolved in dichloromethane (20 ml), and 3-(Triethoxysilyl)propyl isocyanate (1.96 ml) was added dropwise at room temperature. After stirring for 1 hour, the reaction solution was purified using a Florisil column (eluent: CH2Cl2) to obtain 1580 mg of compound (12) as a colorless oil.

1H NMR (CDCl3, 400 MHz) δ 0.60-0.68 (m, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.58-1.68 (m, 2 H), 1.79-1.96 (m, 4 H) ), 3.11-3.25 (m, 6H), 3.38 (t, J = 5.6 Hz, 2H), 3.78-3.85 (m, 8H).

Production example 4: Synthesis of compound (13)

942 mg of 3-Aminopropyltriethoxysilane, 773 mg of 3-(Diethylamino)propionic acid hydrochloride, and 32.6 mg of HOBt were dissolved in 10 ml of dichloromethane, 727 mg of 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified using a Florisil column (eluent: CH2Cl2) to obtain 880 mg of compound (13) as a colorless oil.

1H NMR (CDCl3, 400 MHz) δ 0.58-0.67 (m, 2 H), 1.05 (t, J = 7.2 Hz, 6 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.56-1.63 (m , 2 H), 2.34 (t, J = 5.8 Hz, 2 H), 2.55 (q, J = 7.2 Hz, 4 H), 2.66 (t, J = 7.2 Hz, 2 H), 3.18-3.25 (m, 2 H), 3.81 (q, J = 7.0 Hz, 6 H), 8.54 (br-s, 1H).

Production Example 5: Synthesis of compound (14)

526 mg of 3-Diethylaminopropylamine was dissolved in 10 ml of dichloromethane, 1 ml of 3-(Triethoxysilyl)propyl isocyanate was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain 1480 mg of compound (14) as a colorless oil.

1H NMR (CDCl3, 400 MHz) δ 0.60-0.68 (m, 2 H), 1.02 (t, J = 7.1 Hz, 6 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.57-1.70 (m , 4 H), 2.45-2.57 (m, 6 H), 3.13 (q, J = 7.0 Hz, 2 H), 3.24 (t, J = 6.2 Hz, 2 H), 3.81 (q, J = 7.0 Hz, 6 H), 4.75 (br-s, 1 H), 5.53 (br-s, 1H).

Production Example 6: Synthesis of compound (15)

300 mg of compound (3) was dissolved in 10 ml of ethanol, 30 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After reacting for 3 hours, disappearance of the raw material was confirmed by TLC. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain 168 mg of compound (15) as a colorless oil.

1H NMR (CDCl3, 400 MHz) δ 0.60-0.68 (m, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.50-1.64 (m, 2 H), 2.64 (dd, J =13.8 Hz , 9.0 Hz, 1 H), 3.14 (dd, J =13.8 Hz, 4.2 Hz, 1 H), 3.25 (td, J =13.4 Hz, 6.9 Hz, 2 H), 3.54 (dd, J = 9.0 Hz, 4.2 Hz, 2 H), 3.82 (q, J = 7.0 Hz, 6 H), 6.81 (d, J = 8.5 Hz, 2 H), 7.05 (d, J = 8.5 Hz, 2 H), 7.03(br-d , 2H)

Production Example 7: Synthesis of compound (16)

700 mg of compound (4) was dissolved in 10 ml of ethanol, 77 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After reacting for 1 hour, disappearance of the raw material was confirmed by TLC. The reaction solution was filtered through Celite, the filtrate was concentrated, and the resulting crude product was purified using a Florisil column (eluent: CH2Cl2 : EtOH = 20:1) to obtain compound (16) as 310 mg of a white solid. .

1H NMR (CDCl3, 400 MHz) δ 0.60-0.68 (m, 2 H), 1.23 (t, J = 7.0 Hz, 9 H), 1.45-1.87 (m, 6 H), 1.90-2.07 (m, 2 H ), 2.37 (td, J = 6.8 Hz, 2.1 Hz, 2H), 3.19-3.30 (m, 2H), 3.44 (t, J = 6.6 Hz, 1H), 3.82 (q, J = 7.0 Hz, 6 H) , 5.53 (br-s, 1 H), 6.37 (br-s, 1 H), 7.42 (br-s, 1 H)

Production example 8: Synthesis of compound (17)

550 mg of compound (5) was dissolved in 20 ml of ethanol, 95 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After reacting for 3 hours, disappearance of the raw material was confirmed by TLC. The reaction solution was filtered through Celite, the filtrate was concentrated, and the resulting crude product was purified using a Florisil column (eluent: CH2Cl2 : EtOH = 20:1) to obtain 161 mg of compound (17) as a colorless oil. Ta.

1H NMR (CDCl3, 400 MHz) δ 0.63 (br-t, J = 8.2 Hz, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.31-1.57 (m, 8 H), 1.57-1.68 (m, 3 H), 1.78-1.90 (m, 1 H), 2.70 (t, J = 6.8Hz, 2H), 3.25 (q, J = 6.9 Hz, 2 H), 3.31-3.37 (m, 1 H ), 3.82 (q, J = 7.0 Hz, 6 H), 7.27 (br-s, 1 H).

Production Example 9: Synthesis of compound (18)

1400 mg of compound (6) was dissolved in 10 ml of ethanol, 128 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After reacting for 5 hours, disappearance of the raw material was confirmed by TLC. The reaction solution was filtered through Celite, the filtrate was concentrated, and the resulting crude product was purified using a Florisil column (eluent: CH2Cl2 : EtOH = 20:1) to obtain 470 mg of compound (18) as a colorless oil. Ta.

1H NMR (CDCl3, 400 MHz) δ 0.58-0.68 (m, 2 H), 1.22 (t, J = 7.0 Hz, 9 H), 1.57 (tt, J = 7.8 Hz, 7.2 Hz, 2 H), 1.65- 1.95 (m, 2 H), 2.74-2.82 (m, 1 H), 3.03 (dt, J = 4.5 Hz, 1.7 Hz, 1 H), 3.13-3.26 (m, 2 H), 3.56-3.61 (m, 1H), 3.81 (q, J = 7.0H

Production Example 10: Synthesis of compound (19)

1100 mg of compound (7) was dissolved in 20 ml of ethanol, 183 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After reacting for 2 hours, disappearance of the raw material was confirmed by TLC. The reaction solution was filtered through Celite, the filtrate was concentrated, and the resulting crude product was purified using a Florisil column (eluent: CH2Cl2 : EtOH = 20:1) to obtain 285 mg of compound (19) as a colorless oil. Ta.

1H NMR (CDCl3, 400 MHz) δ 0.62-0.68 (m, 2 H), 1.23 (t, J = 7.0 Hz, 9 H), 1.47 (br-s, 2 H), 1.58-1.68 (m, 2 H ), 2.31 (t, J = 6.0 Hz, 2 H), 3.00 (dd, J = 6.1 Hz, 5.9 Hz, 2 H), 3.26 (dd, J = 12.9 Hz, 7.0 Hz, 2 H), 3.82 (q , J = 7.0 Hz, 6 H), 7.28 (br-s, 1 H).
z, 6 H), 5.04 (s, 2 H), 7.15 (d, J = 7.3 Hz, 2 H), 7.28-7.38 (m, 3 H), 7.44 (s, 1 H), 7.48 (br-t , J = 5.5 Hz, 1 H).

Production Example 11: Synthesis of compound (20)

1600 mg of compound (8) was dissolved in 25 ml of ethanol, 193 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After reacting for 3 hours, disappearance of the raw material was confirmed by TLC. The reaction solution was filtered through Celite, the filtrate was concentrated, and the resulting crude product was purified using a Florisil column (eluent: CH2Cl2 : EtOH = 10:1) to obtain 870 mg of compound (20) as a colorless oil. Ta.

1H NMR (CDCl3, 400 MHz) δ 0.60-0.68 (m, 2 H), 1.23 (t, J = 7.0 Hz, 9 H), 1.58-1.67 (m, 4 H), 1.77 (tt, J = 7.4 Hz , 6.9 Hz, 2 H), 2.23 (t, J = 7.3 Hz, 2 H), 2.36 (t, J = 6.3 Hz, 2 H), 2743 (t, J = 6.8 Hz, 2 H), 3.14-3.21 (m, 2 H), 3.82 (q, J = 7.0 Hz, 6 H), 5.05-5.34 (m, 2 H), 6.05 (br-s, 1 H).

Production Example 12: Synthesis of compound (21)

590 mg of compound (9) was dissolved in 20 ml of ethanol, 153 mg of 10% Pd-C (containing 55% H2O) was added, and the mixture was hydrogenated at room temperature. After reacting for 3 hours, disappearance of the raw material was confirmed by TLC. The reaction solution was filtered through Celite to remove the catalyst, and the filtrate was concentrated to obtain 270 mg of compound (21) as a colorless oil.

1H NMR (CDCl3, 400 MHz) δ 0.60-0.68 (m, 2 H), 1.23 (t, J = 7.0 Hz, 9 H), 1.58-1.67 (m, 4 H), 1.77 (tt, J = 7.4 Hz , 6.9 Hz, 2 H), 2.23 (t, J = 7.3 Hz, 2 H), 2.36 (t, J = 6.3 Hz, 2 H), 2743 (t, J = 6.8 Hz, 2 H), 3.14-3.21 (m, 2 H), 3.82 (q, J = 7.0 Hz, 6 H), 5.05-5.34 (m, 2 H), 6.05 (br-s, 1 H).

Example 1: Production of silicon nanoparticle composition containing cetylpyridinium chloride hydrate using compounds (S1) and (S2)


Solution A was prepared by dissolving 1-butanol (0.8 ml) and dioctyl sodium sulfosuccinate (440 mg) in 20 ml of pure water. Next, solution B was prepared by dissolving cetylpyridinium chloride hydrate (37 mg) in N,N-dimethylformamide (1 ml). Solution A, solution B, and compound (S1) (0.2 ml; manufactured by Tokyo Chemical Industry Co., Ltd.) were added to an eggplant flask (volume 50 ml), and the mixture was stirred at room temperature for 1 hour. Next, Compound (S2) (0.1 ml; manufactured by Tokyo Kasei) was added, and the mixture was further stirred for 1 hour. The resulting mixed solution is subjected to dialysis treatment for 48 hours using a dialysis membrane (Float-A-lyzer (registered trademark) G2 molecular weight cutoff (MWCO); 20 kD, manufactured by Spectrum Laboratories). The dialyzed solution was sterile filtered using a 0.22 μm filter (syringe filter manufactured by Techno Lab SC (product number TLMC25022)).

Example 2: Production of silicon nanoparticle composition containing cetylpyridinium chloride hydrate using compound (S3)

Solution A (5.2 ml), solution B (0.25 ml), and compound (S3) (47.6 μl; manufactured by Sigma-Aldrich) described in Example 1 were added to a sample tube (capacity 30 ml) and stirred at room temperature for 2 hours. did. The resulting mixed solution is subjected to dialysis treatment for 48 hours using a dialysis membrane (Float-A-lyzer (registered trademark) G2 molecular weight cutoff (MWCO); 20 kD, manufactured by Spectrum Laboratories). The dialyzed solution was sterile filtered using a 0.22 μm filter (syringe filter manufactured by Techno Lab SC (product number TLMC25022)).

Examples 3 to 10
The cetylpyridinium chloride hydrate-containing silicones of Examples 3 to 9 below were prepared in the same manner as in Example 1 by using the following silicon compounds (S4) to (S10) in place of compound (S1). A nanoparticle composition was produced.

The silicon compounds used in Examples 3 to 10 are shown in Table 3 below.

Example 11: Production of silicon nanoparticle composition containing cetylpyridinium chloride hydrate using compounds (S3) and (S2)

Solution A (5.2 ml), solution B (0.25 ml), and compound (S3) (47.6 μl; manufactured by Sigma-Aldrich) described in Example 1 were added to a sample tube (volume 30 ml) and stirred at room temperature for 1 hour. did. Next, compound (S2) (25 μl; manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added, and the mixture was further stirred for 1 hour. The resulting mixed solution is subjected to dialysis treatment for 48 hours using a dialysis membrane (Float-A-lyzer (registered trademark) G2 molecular weight cutoff (MWCO); 20 kD, manufactured by Spectrum Laboratories). The dialyzed solution was sterile filtered using a 0.22 μm filter (syringe filter manufactured by Techno Lab SC (product number TLMC25022)).

Example 12: Production of silicon nanoparticle composition containing cetylpyridinium chloride hydrate using compound (S3) and compound (10)

Solution A (5.2 ml), solution B (0.25 ml), and 50 μL of compound (S1) described in Example 1 were added to a sample tube (volume 30 mL), and the mixture was stirred at room temperature for 1 hour. Next, 40 mg of Example Compound (10) was added and further stirred for 1 hour. The resulting mixed solution was subjected to dialysis treatment for 48 hours using a dialysis membrane (Float-A-lyzer (registered trademark) G2 MWCO: 20 kD, manufactured by Spectrum Laboratories). The dialyzed solution was sterile filtered using a 0.22 μm filter (Durapore and Millex, both registered trademarks, manufactured by Merck Millipore).

Example 13: Production of silicon nanoparticle composition containing cetylpyridinium chloride hydrate using compound (S3) and compound (11)

Solution A (5.2 ml), solution B (0.25 ml), and 50 μL of compound (S1) described in Production Example 1 were added to a sample tube (volume 30 mL) and stirred at room temperature for 1 hour. Next, 40 mg of Example Compound (11) was added and further stirred for 1 hour. The resulting mixed solution was subjected to dialysis treatment for 48 hours using a dialysis membrane (Float-A-lyzer (registered trademark) G2 MWCO: 20 kD, manufactured by Spectrum Laboratories). The dialyzed solution was sterile filtered using a 0.22 μm filter (Durapore and Millex, both registered trademarks, manufactured by Merck Millipore).

The drug concentration, drug loading rate, and average particle diameter of the cetylpyridinium chloride hydrate-containing silicon nanoparticle compositions produced in Examples 1 to 11 were measured. The results are shown in Table 4.

Cetylpyridinium chloride concentration was measured by HPLC.
(a) A silicon nanoparticle composition containing cetylpyridinium chloride hydrate was ultrafiltered using a MWCO 300K ultrafiltration membrane (manufactured by Pall Corporation). The amount of unloaded cetylpyridinium chloride was determined by measuring the concentration of cetylpyridinium chloride in the ultrafiltrate by HPLC.
The loading rate was calculated using the following formula.

The average particle diameter was measured as an effective diameter by dynamic light scattering using Zetasizer Nano ZS (manufactured by Malvern).

Next, a method for producing a drug-containing silica nanoparticle composition will be described from an experimental example (antibacterial agent).

Experimental example

Experimental Example 1: Production of levofloxacin-containing silicon nanoparticle composition (LVF-NPs) Solution A was prepared by dissolving 1-butanol (0.8 ml) and dioctyl sodium sulfosuccinate (440 mg) in 20 ml of pure water. Next, solution B was prepared by dissolving levofloxacin (37.4 mg) in N,N-dimethylformamide (1 ml). Solution A, solution B, and triethoxyvinylsilane (0.2 ml; manufactured by Tokyo Chemical Industry Co., Ltd.) were added to an eggplant flask (volume 50 ml), and the mixture was stirred at room temperature for 1 hour. Next, (3-aminopropyl)triethoxysilane (0.1 ml; manufactured by Tokyo Kasei) was added and stirred for an additional hour. The resulting mixed solution is subjected to dialysis treatment for 48 hours using a dialysis membrane (Float-A-lyzer (registered trademark) G2 molecular weight cutoff (MWCO); 20 kD, manufactured by Spectrum Laboratories). The dialyzed solution is sterile filtered using a 0.22 μm filter (syringe filter manufactured by Techno Lab SC (product number TLMC25022)) to obtain the title composition.

Experimental Example 2: Production of ciprofloxacin-containing silica nanoparticle composition (CPFX-NPs) Solution A was prepared by dissolving 1-butanol (0.8 ml) and dioctyl sodium sulfosuccinate (440 mg) in 20 ml of pure water. Next, solution B was prepared by dissolving ciprofloxacin (34.3 mg) in N,N-dimethylformamide (1 ml). Solution A, solution B, and triethoxyvinylsilane (0.2 ml; manufactured by Tokyo Chemical Industry Co., Ltd.) were added to an eggplant flask (volume 50 ml), and the mixture was stirred at room temperature for 1 hour. Next, (3-aminopropyl)triethoxysilane (0.1 ml; manufactured by Tokyo Kasei) was added and stirred for an additional hour. The resulting mixed solution is subjected to dialysis treatment for 48 hours using a dialysis membrane (Float-A-lyzer (registered trademark) G2 molecular weight cutoff (MWCO); 20 kD, manufactured by Spectrum Laboratories). The dialyzed solution is sterile filtered using a 0.22 μm filter (syringe filter manufactured by Techno Lab SC (product number TLMC25022)) to obtain the title composition.

Experimental Example 3: Production of clinafloxacin-containing silica nanoparticle composition (CLFX-NPs) 1-butanol (0.8 ml) and dioctyl sodium sulfosuccinate (440 mg) were dissolved in 20 ml of pure water to prepare solution A. Next, solution B was prepared by dissolving clinafloxacin (37.9 mg) in N,N-dimethylformamide (1 ml). Solution A, solution B, and triethoxyvinylsilane (0.2 ml; manufactured by Tokyo Chemical Industry Co., Ltd.) were added to an eggplant flask (volume 50 ml), and the mixture was stirred at room temperature for 1 hour. Next, (3-aminopropyl)triethoxysilane (0.1 ml; manufactured by Tokyo Kasei) was added and stirred for an additional hour. The resulting mixed solution is subjected to dialysis treatment for 48 hours using a dialysis membrane (Float-A-lyzer (registered trademark) G2 molecular weight cutoff (MWCO); 20 kD, manufactured by Spectrum Laboratories). The dialyzed solution is sterile filtered using a 0.22 μm filter (syringe filter manufactured by Techno Lab SC (product number TLMC25022)) to obtain the title composition.

Explanation of efficacy

[Efficacy 1]
Antibacterial activity evaluation test of the cetylpyridinium chloride hydrate-containing silicon nanoparticle composition produced in Example 1 Purpose: Evaluate the antibacterial activity of Example 1 against the following test bacterial strains Test strain: S. aureus FDA 209P ( MSSA), E. coli ATCC 8739,
S. aureus MU-3 (MRSA), P. aeruginosa ATCC 27853
Test method: Broth microdilution method according to Clinical Laboratory Standards Institute
(i) Apply the strain stored at -80°C to MHII agar and culture at 35°C for 16-20 hr.
(ii) Suspend the cultured bacteria in MHIIB to a McFarland concentration of 0.5, dilute the suspension 100 times, and prepare the bacterial count in MHIIB to approximately 10 ⁶ CFU/mL.
(iii) After preparing each compound stock solution to the top dose shown in the next section using MHIIB, repeat the 2-fold dilution using MHIIB to prepare a compound-containing medium.
(iv) Dispense 50 μL of each compound-containing medium from (iii) into a 96-well plate, and inoculate with 50 μL of the bacterial solution from (ii). Incubate at 35℃ for 20-24 hours.

Judgment method: Minimum Inhibitory is the lowest concentration at which no bacterial growth is observed with the naked eye.
CPC ・・・・ Cetylpyridinium chloride hydrate

[Efficacy 2]
Evaluation of antibacterial activity of coating materials;
Test purpose: Evaluate the antibacterial activity of the cetylpyridinium chloride hydrate-containing silicon nanoparticle composition (ACPC-NPs) produced in Example 1 coated on various materials.

Test strain: S. aureus FDA 209P (MSSA), E. coli ATCC 8739,
S. aureus MU-3 (MRSA), P. aeruginosa ATCC 27853
Test method:
(i) Apply the strain stored at -80°C to MHII agar and incubate at 35°C for 16-20 hours.
(ii) Suspend the cultured bacteria in MHIIB to a McFarland concentration of 0.5, and dilute appropriately with MHIIB to obtain a bacterial count of approximately 104 CFU/ml.
(iii) Drop 0.2 mL of this as a test bacterial solution onto MHII agar, and place a test piece (50 mm x 50 mm) on top of it. (The bacterial solution will spread naturally due to the weight of the test piece.) Cover the Petri dish and incubate at 35℃ for 20-24 hours.
Judgment method: It is judged that there is an effect when colony growth is clearly inhibited compared to the unprocessed test piece.

[Efficacy 3]
Drug elution from the nanoparticle composition-coated materials produced in Experimental Examples 1 to 3 and Example 1 was evaluated.
Test conditions Material: Titanium metal (5 x 5 cm)
Amount of applied drug: 100μg/25cm2 (4μg/cm2)
Processing method: After dropping, air dry Test container: Glass Petri dish Test solution: PBS pH7.4, 20ml
Shaking conditions: 37℃, 10rpm
Sampling points; 1hr, 2hr, 4hr, 8hr, 24hr
Evaluated NPs samples;

Drug elution rate, (%)

[Efficacy 4]
The sustained antibacterial activity of the cetylpyridinium chloride hydrate-containing silicon nanoparticle composition (ACPC-NPs) produced in Example 1 was evaluated by the experiment shown below.
Using an untreated titanium plate (1) and a titanium plate (2) coated with a silicon nanoparticle composition containing cetylpyridinium chloride hydrate, a sample of methicillin-resistant Staphylococcus aureus MRSA (S. aureus MU3) was tested. The sustained antibacterial activity using growth as an index was evaluated according to the following test method.
Test method:
(i) Test piece (1) (untreated titanium plate 50 mm x 50 mm) and test piece (2) (titanium plate 50 mm x 50 mm coated with the cetylpyridinium chloride hydrate-containing silicon nanoparticle composition of Example 1) ) into a 9cm Petri dish, add 20ml of PBS, and shake at 37℃ and 55rpm.
(ii) Replace the PBS with fresh one every day, take out each test piece on days 1, 3, 5, 7, 14, 21, and 28 after the start of shaking, rinse the surface with PBS, and then leave it naturally. The dried product is used for antibacterial activity evaluation.
(iii) Spread the S. aureus MU-3 strain stored at -80℃ onto Mueller Hinton II agar (MHIIA), culture at 35℃ for 16 to 20 hours, and then transfer the cultured bacteria to Mueller Hinton II agar (MHIIA). Suspend in Muller Hinton II broth (MHIIB) to a McFarland turbidity of 0.5, and dilute as appropriate so that the number of bacteria is approximately 104 CFU (colony forming unit)/ml. liquid).
(iv) Drop 0.2ml of the test bacteria solution onto MHIIA, place each test piece on top of it, cover it, and incubate at 35℃.
Incubate for 20-24 hours.
(v) The growth of bacteria on test piece (1) is defined as +++, and when the growth of bacteria on test piece (2) is at the same level as that of test piece (1), +++ is approximately the same as on test piece (1). If the number of colonies is 50% or less of 1), it is evaluated as ++, if the number of colonies is approximately from a few to 50 or less, it is evaluated as +, if no bacterial growth is observed, it is evaluated as -, and if it is - to ++, it is evaluated as antibacterial activity. It is determined that there is.
Test results;
As shown in Table 9, bacterial growth was observed on the test piece (1) from the first day of the test. In contrast, no bacterial growth was observed in test piece (2) even on the 14th day after the start of the test. Although a small amount of bacterial growth was observed on the 21st day, the growth was still slight on the 28th day.
In this test, sustained antibacterial activity was observed on the titanium plate surface by coating with a silicon nanoparticle composition containing cetylpyridinium chloride hydrate.

[Efficacy 5]
Antiviral activity evaluation test of the silicon nanoparticle composition containing cetylpyridinium chloride hydrate produced in Example 1 *Conducted at the Kobe Test Center of the Japan Textile Products Quality Technology Center, a general incorporated foundation Test conditions:
Test virus: Influenza virus A
Test sample: (i) Silicon nanoparticle composition aqueous solution containing 0.06% cetylpyridinium chloride hydrate (Example 1)
(ii) Aqueous solution of silicon nanoparticle composition containing 0.006% cetylpyridinium chloride hydrate (1/10 concentration of Example 1)
Test conditions: virus suspension: test sample = 1:9
Working temperature 25℃
Action time: 15 seconds, 5 minutes Infectious titer measurement method: Plaque measurement method Test results

The present invention exhibits sustained antiviral and antibacterial or bactericidal effects. Nanoparticle compositions are provided that include cetylpyridinium chloride hydrate and a silicon compound. The present invention can also be used in a drug delivery system for preventing and/or treating infectious diseases using medical materials or medical devices, orthopedic medicine, or medical devices carrying the composition.

Claims (6)

Cetylpyridinium chloride hydrate and a specific silicon compound represented by the following general formula (I) are mixed to form micelles, and then made into nanoparticles to obtain a composition in the form of nanoparticles. , Method for Preparing Nanoparticle Compositions.

[In formula (I),
A represents a bond or lower alkylene; R _{1 ,} R ₂ and R ₃ are each independently,

Shows O-R ₅ ;

_R5 is
(1) Lower alkyl, or (2) lower alkanoyl;
_R4 is
(1) Lower alkyl,
(2) lower alkenyl,
(3) Phenyl,
(4) amino which may be substituted with the same or different 1 to 2 R ₆ ,
(5) R ₆ -CONH, or (6) indicates cyano
_R6 is
(1) Lower alkyl optionally substituted with 1 to 2 R _7s that are the same or different;
(2) amino optionally substituted with the same or different 1 to 2 R ₈ ;
(3) Indicates silyl lower alkyl which may be substituted with the same or different 1 to 3 lower alkoxy.
_R7 is
(1) Amino which may be substituted with the same or different 1 to 2 lower alkyls,
(2) phenyl optionally substituted with hydroxy;
(3) Carbamoyl,
(4) imidazolyl optionally substituted with benzyl,
(5) represents guanidino which may be substituted with carboxy or (6) benzyloxycarbonyl;
_R8 is
(1) represents amino lower alkyl (herein, amino may be substituted with 1 to 2 lower alkyls that are the same or different), or (2) carboxy. ] In the compound of formula (I),
A represents a bond or C _1-6 alkylene;
R ₁ , R ₂ and R ₃ are each independently,
Shows O-R ₅ ;

R ₅ is
(1) C _1-6 alkyl, or (2) C _1-6 alkanoyl;
R ₄ is
(1) C _1-8 alkyl,
(2) C _2-4 alkenyl,
(3) Phenyl,
(4) amino optionally substituted with one _R8 ,
(5) R ₆ -CONH, or (6) indicates cyano;
R ₆ is
(1) Lower alkyl optionally substituted with 1 to 2 R _7s that are the same or different;
(2) amino optionally substituted with the same or different 1 to 2 R ₈ ;
(3) Silyl C _1-6 which may be substituted with the same or different 1 to 3 lower alkoxy groups
Indicates alkyl;
R ₇ is
(1) Amino which may be substituted with the same or different 1 to 2 C _1-6 alkyl,
(2) phenyl substituted with hydroxy,
(3) Carbamoyl,
(4) Benzyl imidazolyl,
(5) represents carboxy, or (6) guanidino;
R ₈ represents amino-C _1-6 alkyl (wherein amino may be substituted with the same or different 1 to 2 C _1-6 alkyl); or two R _8s are bonded together. A compound which, together with nitrogen, may form a saturated or unsaturated 3- to 12-membered monocyclic or bicyclic heterocycle containing at least one nitrogen as a ring heteroatom; A method for producing the composition according to claim 1. In the compound of formula (I),
A represents C _1-6 alkylene;
R ₁ , R ₂ and R ₃ each independently represent O-R ₅ ;
R ₅ represents C _1-6 alkyl;
R ₄ indicates R ₆ -CONH;
R ₆ is
(1) C _1-6 alkyl which may be substituted with the same or different 1 to 2 R _7s , or (2) amino which may be substituted with the same or different 1 to 2 R _8s ;
R ₇ is
(1) Amino which may be substituted with two same or different C _1-6 alkyls,
(2) phenyl substituted with hydroxy,
(3) Carbamoyl,
(4) Benzyl imidazolyl,
(5) represents carboxy, or (6) guanidino;
Any of claims 1 or 2, wherein R ₈ is a compound representing amino-C _1-6 alkyl (wherein amino may be substituted with the same or different 1 to 2 C _1-6 alkyl). A method for producing the composition described in Crab. 2. The method for producing a nanoparticle composition according to claim 1, wherein after forming the micelles, dialysis is performed and further sterile filtration is performed to obtain a composition in the form of sterilized nanoparticles. A method of utilizing the composition produced by the manufacturing method according to claim 1, wherein the composition is carried on a preventive tool and/or a medical tool used for preventing and/or treating infectious diseases. A method for producing a composition by the production method according to claim 1 and supporting it on a medical material or medical device.